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Relapsed or Refractory NeuroblastomaPhase 1NCT02761915

A Phase I Trial of Anti-GD2 T-cells (1RG-CART)

A Phase 1 study testing Leukapheresis, Cyclophosphamide and Fludarabine in people with Relapsed or Refractory Neuroblastoma, run by Cancer Research UK at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The purpose of this first in human study is to determine the safety and feasibility of 1RG-CART therapy in patients with relapsed or refractory neuroblastoma. 1RG-CART therapy is a novel immunotherapy under investigation in which patients have their T-cells (a type of white blood cell) collected and modified in the… Read more about this study

Who is it for?
Ages 1 year and older
Conditions the study is for
Relapsed or Refractory Neuroblastoma
What is being tested?
Leukapheresis, Cyclophosphamide and Fludarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
1 siteUnited Kingdom
Study dates
29 Feb 2016to 16 Dec 2020
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Written informed consent* for leukapheresis/venepuncture and transduction of T-cells.
  • Suitability for leukapheresis/venepuncture defined as:
  • Negative for human immunodeficiency virus (HIV), human T-cell lymphotropic virus (HTLV) 1, HTLV 2, syphilis and hepatitis B.
  • Minimum T-lymphocyte count of 0.25x10^9/L.
  • Relapsed or refractory neuroblastoma (the patient must have evidence of active disease even if they do not currently require active treatment).
  • Patients must have at least one lesion that can be evaluated for response by imaging and/or diffuse bone marrow infiltration.
Show all 17Show fewer
  • Adequate renal function, defined as a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m^2 (corrected).
  • Karnofsky score ≥60% if ≥16 years old or Lansky performance score of ≥60% if <16 years old
  • *Informed consent from the patient's parent or legal guardian is required for all patients under 16 years of age. Patients under 16 years of age may also provide written assent to take part in the trial.
  • Histologically proven neuroblastoma, which is relapsed or refractory to conventional treatment.
  • Patients must have at least one lesion that can be evaluated for response by imaging and/or diffuse bone marrow infiltration.
  • Aged ≥12 months at the time written consent is given for the dose escalation phase or aged ≥6 months at the time written consent is given for the dose expansion phase of the trial.
  • Life expectancy of at least two months.
  • Karnofsky score ≥60% if ≥16 years old or Lansky performance score of ≥60% if <16 years old
  • Adequate renal function, defined as a GFR of ≥30 mL/min/1.73m^2 (corrected).
  • Written (signed and dated) informed consent to the main trial* and be capable of co-operating with treatment and follow-up.
  • *Informed consent from the patient's parent or legal guardian is required for all patients under 16 years of age. Patients under 16 years of age may also provide written assent to take part in the trial.

Who cannot join

  • Patients should not meet (or be anticipated to meet) any of the exclusion criteria for the main trial, see criteria below
  • Eligibility Criteria for the Main Trial
  • Patients who have received anti-GD2 antibody treatment within the previous 2 weeks (based on the half life of ch14.18 antibody being 1-3 days in children); patients who have received dinutuximab or other anti-GD2-directed antibody may need a longer washout period.
  • Patients for whom rituximab is contraindicated due to severe previous hypersensitivity or any other reason.
  • Patients must have recovered from the acute reversible effects of any previous therapy before infusion of the 1RG-CART.
  • Current CNS involvement (including intradural meningeal involvement). Patients who previously had CNS involvement but have been surgically treated and disease free for ≥2 months are eligible.
Show all 17Show fewer
  • Co-existing chronic progressive neurological disease.
  • Airway compromise by direct tumoural invasion or compression.
  • Patients with active autoimmune disease requiring systemic treatment.
  • Patients who are taking or likely to require high dose systemic corticosteroids or other immunosuppressive therapy (patients on steroid replacement therapy are eligible).
  • Patients at high medical risk because of non-malignant systemic disease including active uncontrolled infection.
  • Major surgery from which the patient has not yet recovered.
  • Female patients who are able to become pregnant (or already pregnant or lactating). However, those patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral; injected or implanted hormonal contraception and condom; have an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective at the first administration of the lymphodepleting regimen or at administration of the 1RG-CART (whichever comes first), throughout the trial and for six months afterwards are considered eligible. Note that for female patients who receive cyclophosphamide or rituximab, the contraceptive period should be extended to 12 months after cyclophosphamide/rituximab administration.
  • Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] effective at the first administration of the lymphodepleting regimen or at administration of the 1RG-CART [whichever comes first], throughout the trial and for six months afterwards). Men with pregnant or lactating partners must be advised to use barrier method contraception (for example: condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
  • Known to be serologically positive for hepatitis B, hepatitis C or HIV.
  • Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  • Is a participant in another clinical trial of an investigational medicinal product (CTIMP). Participation in an observational trial or in the follow-up phase of a CTIMP would be acceptable.

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site
  • University College London Institute of Child Health & Great Ormond Street Hospital

    London, WC1N 3JH

Other trials in United Kingdom

About this study

Official title: A Cancer Research UK Phase I Trial of Anti-GD2 Chimeric Antigen Receptor (CAR) Transduced T-cells (1RG-CART) in Patients With Relapsed or Refractory Neuroblastoma

The purpose of this first in human study is to determine the safety and feasibility of 1RG-CART therapy in patients with relapsed or refractory neuroblastoma. 1RG-CART therapy is a novel immunotherapy under investigation in which patients have their T-cells (a type of white blood cell) collected and modified in the laboratory, before they are given back to the patient. The T-cells are modified to express a chimeric antigen receptor (CAR) which targets disialoganglioside (GD2), a marker expressed on the surface of neuroblastoma cells.

Read the detailed description

The purpose of this trial is to explore the safety and feasibility of deploying autologous anti-GD2 CAR T-cells for the immunotherapy of neuroblastoma. The CAR T-cell trials employing second generation receptors and lymphodepleting conditioning regimes have produced objective clinical responses in patients with relapsed leukaemias. The trial aims to evaluate similar CAR T-cells but directed against the antigen GD2. Neuroblastoma is well suited to this form of targeted therapy because of the homogeneous and almost universal expression of GD2 on the surface of neuroblastoma cells, and because of the poor prognosis of eligible patients.

1RG-CART will be administered intravenously. As the CAR T-cells are designed to survive and proliferate on encountering antigen, no direct relationship is anticipated between cell dose and either efficacy or toxicity. Rather, clinical benefit is more likely to be observed in those patients in whom in vivo expansion successfully occurs. A possible key determinant of expansion will be prior lymphodepletion of the patients. For this reason this trial is designed to evaluate a phased introduction of lymphodepletion in successive patient cohorts, rather than T-cell dose escalation. Only if there is insufficient expansion of T-cells following full lymphodepletion will the T-cell dose be escalated. Rituximab (MabThera®) will be used as a rescue medication only when necessary, and will be considered a non-investigational medicinal product (NIMP) in this trial.

Being tested
Leukapheresis, Cyclophosphamide, Fludarabine, 1RG-CART
Keywords
Neuroblastoma, Immunotherapy, 1RG-CART, Cyclophosphamide, Fludarabine, CAR T-cells, Anti-GD2, GD2, CAR, Chimeric Antigen Receptor, Cytokine Release Syndrome
Medical subject headings
Recurrence, Neuroblastoma, Cytokine Release Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT02761915
Study groupRoleWhat they receive
Dose Level 1OtherPatients in Dose Level 1 will receive 1x10^7 1RG-CART/m^2 intravenously (IV) on Day 0.
Receives: Other: Leukapheresis; Genetic: 1RG-CART
Dose Level 2OtherPatients in Dose Level 2 will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -4 to -1) followed by 1x10^7 1RG-CART/m^2 IV on Day 0.
Receives: Other: Leukapheresis; Drug: Cyclophosphamide; Genetic: 1RG-CART
Dose Level 3OtherPatients in Dose Level 3 will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m^2/day of fludarabine for five days (Days -8 to -4), followed by 1x10^7 1RG-CART/m^2 IV on Day 0.
Receives: Other: Leukapheresis; Drug: Cyclophosphamide; Drug: Fludarabine; Genetic: 1RG-CART
Dose Level 4OtherPatients in Dose Level 4 will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m^2/day of fludarabine for five days (Days -8 to -4), followed by 1x10^8 1RG-CART/m^2 IV on Day 0.
Receives: Other: Leukapheresis; Drug: Cyclophosphamide; Drug: Fludarabine; Genetic: 1RG-CART
Dose Level 5OtherIf the required level of 1RG-CART survival is not reached, a further cohort of patients (Dose Level 5) will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m^2/day of fludarabine for five days (Days -8 to -4), followed by 5-10x10^8 1RG-CART/m^2 IV which could be be split over two days (Day 0 and Day 1).
Receives: Other: Leukapheresis; Drug: Cyclophosphamide; Drug: Fludarabine; Genetic: 1RG-CART
Patients who underwent leukapheresis but did not proceed to receive any IMPOtherPatients who were enrolled and underwent leukapheresis but who did not receive any IMP.
Receives: Other: Leukapheresis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. To Evaluate the Feasibility of 1RG-CART Therapy in Patients With Relapsed or Refractory Neuroblastoma

    Feasibility of 1RG-CART therapy assessed as the number of patients who commence T-cell processing and are subsequently evaluable for 1RG-CART engraftment at Day 14.

    Measured: Day 14

  2. Safety and Tolerability of 1RG-CART Therapy

    Number of serious adverse events, non-serious adverse events and adverse events that are related to fludarabine, cyclophosphamide or 1RG-CART.

    Measured: From the time of informed consent to leukapheresis until withdrawal from the trial or start of other anti-cancer therapy (a median time period of 132 days [range 68 to 301 days])

  3. To Determine Recommended Phase II Regimen by Assessing the Number of DLTs at Each Dose Level

    Number of dose limiting toxicities (DLTs) at each dose level.

    Measured: From the time of informed consent to leukapheresis until withdrawal from the trial or start of other anti-cancer therapy (a median time period of 132 days [range 68 to 301 days])

Secondary outcomes (6)
  1. 1RG-CART Counts in the Peripheral Blood

    Number of patients with 1RG-CART levels in peripheral blood above the limit of quantification for the assay (10 cells/µL) by flow cytometry.

    Measured: From Day 0 until end of trial (median 38.5 days, range 20 to 233 days)

  2. Assessment of Tumour Response From Baseline (RECIST)

    Assessment of best tumour response from baseline according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

    Measured: Day 28, 2 months and 4 months

  3. Assessment of Tumour Response From Baseline (irRC)

    Assessment of best tumour response from baseline according to Immune Related Response Criteria (irRC).

    Measured: Day 28, 2 months and 4 months

  4. Assessment of Tumour Response From Baseline (INRC)

    Assessment of best tumour response from baseline according to International Neuroblastoma Response Criteria (INRC).

    Measured: Day 28, 2 months and 4 months

  5. To Evaluate Anti-tumour Activity (Progression Free Survival)

    Progression free survival (progression by RECIST criteria).

    Measured: Up to 2 years

  6. To Evaluate Anti-tumour Activity (Overall Survival)

    Overall survival.

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 May 2016 (estimated)
  2. Study start29 Feb 2016
  3. Primary completion16 Dec 2020
  4. Study completion16 Dec 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02761915
Sponsor's protocol ID
CRUKD/15/001
Other IDs
2013-004554-17
Status last verified
Jul 2021
First submitted
24 Feb 2016
Last updated
17 Aug 2021
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Straathof K, Flutter B, Wallace R, Jain N, Loka T, Depani S, Wright G, Thomas S, Cheung GW, Gileadi T, Stafford S, Kokalaki E, Barton J, Marriott C, Rampling D, Ogunbiyi O, Akarca AU, Marafioti T, Inglott S, Gilmour K, Al-Hajj M, Day W, McHugh K, Biassoni L, Sizer N, Barton C, Edwards D, Dragoni I, Silvester J, Dyer K, Traub S, Elson L, Brook S, Westwood N, Robson L, Bedi A, Howe K, Barry A, Duncan C, Barone G, Pule M, Anderson J. Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. Sci Transl Med. 2020 Nov 25;12(571):eabd6169. doi: 10.1126/scitranslmed.abd6169.

    PubMed 33239386
  • Li X, Li W, Xu L, Song Y. Chimeric antigen receptor-immune cells against solid tumors: Structures, mechanisms, recent advances, and future developments. Chin Med J (Engl). 2024 Jun 5;137(11):1285-1302. doi: 10.1097/CM9.0000000000002818. Epub 2023 Aug 28.

    PubMed 37640679

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Leukapheresis, Cyclophosphamide and Fludarabine in people with Relapsed or Refractory Neuroblastoma, run by Cancer Research UK at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Aug 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

To Evaluate the Feasibility of 1RG-CART Therapy in Patients With Relapsed or Refractory Neuroblastoma (time frame: Day 14). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02761915, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Aug 2021.

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